JP2018521055A - Sacbitril calcium salt - Google Patents

Abstract

  The present invention relates to a polymorphic form of the calcium salt of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenyl-methyl) -4-amino- (2R) -methylbutanoic acid ethyl ester About. The calcium salt of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenyl-methyl) -4-amino- (2R) -methylbutanoic acid ethyl ester is effective in inhibiting neutral endopeptidase. Useful in the treatment of various conditions and disorders that respond.

Description

  The present disclosure generally relates to N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377, sacbitril). (Also known as) calcium salts. The present disclosure specifically relates to polymorphic forms of the calcium salt of AHU377. The present disclosure also generally relates to pharmaceutical compositions comprising the polymorphic forms, polymorphs in the treatment of various conditions and disorders responsive to inhibition of neutral endopeptidase (EC 3.4.24.11). It relates to methods of using sexual forms as well as methods for obtaining said polymorphic forms.

  Polymorphism is the presence of different crystalline forms of a single compound in the solid state. Thus, polymorphs have the same molecular formula but unique physical properties. Thus, a single compound can have different polymorphic forms, each form having different specific physical properties, such as solubility, melting point, and / or X-ray diffraction pattern.

  Biaryl-substituted phosphonic acid derivatives are known in the art and are useful as neutral endopeptidase (NEP) inhibitors, eg, as inhibitors of ANF degrading enzymes in mammals, thereby making more Inhibiting the degradation of ANF to less active metabolites prolongs and enhances the diuretic, natriuretic and vasodilatory properties of ANF in mammals. Thus, NEP inhibitors are conditions and disorders that respond to inhibition of neutral endopeptidase (EC 3.4.24.11), particularly cardiovascular disorders such as renal failure including hypertension, edema and salt retention, pulmonary edema and congestion. It is particularly useful for the treatment of congenital heart failure.

  Some dicarboxylic acid dipeptide neutral endopeptidase (NEP) inhibitors are described in GM Kasander et al., J. Med. Chem. 1995, 38, 1689-1700, "Dicarboxylic Acid Dipeptide Neutral Endopeptidase (NEP) inhibitors" Has been. Said document discloses the sodium salt of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester. The compound is actually N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid which is the actual NEP inhibitor But for convenience of reference, hereinafter also referred to as NEP inhibitors, the term also includes any of the calcium salt modifications described herein.

  US Pat. No. 5,217,996 also describes N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenyl-phenylmethyl) -4-amino- (2R) -methylbutanoic acid. The ethyl ester and its sodium salt form are disclosed.

  WO 2008/031567 generally describes ethyl N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoate. Although a reaction scheme for obtaining the calcium salt of the ester is disclosed, the method for preparing it is not disclosed in detail.

  WO 2008/083967 discloses that the calcium salt is ethyl N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoate. The preferred salt of the ester is disclosed.

  The prior art does not describe any specific physical form of AHU377 calcium salt or methods of preparation of such forms. It is therefore necessary to develop a defined physical form of the calcium salt of AHU377. It is therefore important to provide the calcium salt of AHU377, which is a physical form that can be reliably prepared and purified on a large or commercial scale. Its physical form should ideally be stable and not decompose upon storage. The selected physical form must also be stable while the drug substance is manufactured as a formulation suitable for the selected intended route of administration. In that regard, it may be necessary to consider the physical properties of the physical form that result in handling characteristics or higher bulk density. In particular, non-hygroscopicity is particularly important for obtaining good flow properties.

  The properties of the final product should also be predictable and reliably reproducible. For example, materials obtained in an inconsistent manner must be carefully monitored, for example when the water content varies from batch to batch. This results in complex drug substance handling, manufacturing, analysis and formulation.

  One form, for example a crystalline form, may exhibit properties that are considered suitable, while another form also has properties that may lead to successful development of the drug by taking appropriate measures. Can do. Thus, the determination as to whether a compound is suitable for commercialization depends on the discovery of a (eg, crystalline) form of the compound that has the proper balance of desirable characteristics.

  Pharmaceutical formulations are affected by the delivery rate or bioavailability of the pharmaceutically active substance in different (eg, crystalline or amorphous) forms or polymorphs. This relationship between different forms or polymorphs and bioavailability is known in the pharmaceutical industry and across a wide range of pharmaceutical products.

  The inventors have been the subject of their research work to develop advantageous forms of calcium salts and methods for their preparation.

  In one aspect, the invention provides, inter alia, formula (I)

The crystallinity of the calcium salt of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) having It relates to a method for preparing an amorphous form.

  In a further aspect, inter alia, formula (I)

In a process for preparing a calcium salt of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester having A solution of a sodium salt of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester, calcium salt, In particular, a method is provided which comprises reacting with a calcium halide, preferably CaCl ₂ .

In a further aspect, an aqueous solution of a sodium salt of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester is obtained by using a calcium salt. In particular, a method is provided comprising reacting with an aqueous solution of calcium halide, preferably CaCl ₂ .

  In one aspect, the invention provides, inter alia, formula (I)

A crystalline form of the calcium salt of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester having .

In another aspect of the invention, the calcium salt of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester and N Calcium salt of said compound in a ratio of 2- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester and calcium 2: 1 A process for preparing, inter alia, those having the formula (I) shown above, comprising N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino A solution of the sodium salt of-(2R) -methylbutanoic acid ethyl ester is dissolved in an aqueous solvent, for example a calcium salt, in particular in water, Um, preferably comprises reacting a solution of CaCl _2, a method is provided.

Embodiments of these crystalline forms of AHU377 calcium salt include those characterized herein as modification A, modification B (particularly preferred), modification C and modification H _B (preferred).

  In a further aspect, the present invention provides N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester of formula (I) An amorphous form of the calcium salt is provided.

  Each crystalline or amorphous form can be characterized by one or more or all peaks in the X-ray diffraction pattern described in its corresponding later figures.

  In another aspect of the present invention, there is provided a pharmaceutical composition comprising a crystalline or amorphous form described herein and one or more pharmaceutically acceptable carriers or additives. . The composition may comprise at least 50, 60, 70, 80 or 90% by weight of a crystalline form of the compound of formula (I), based on the weight of the compound of formula (I) in the composition. In another aspect of the invention, the pharmaceutical composition comprises an additional therapeutic agent.

  One prevalence of polymorphic crystalline forms can be determined by quantification of characteristic signals in X-ray powder diffraction (XRPD) and XRPD spectra.

  In a further aspect there is provided a crystalline or amorphous form or a pharmaceutical composition as described above for use in the treatment or prevention of conditions and disorders responsive to inhibition of neutral endopeptidase (EC 3.4.24.11). Is done. In one aspect of the invention, such crystalline forms, or the like thereof, for the manufacture of a medicament for treating or preventing conditions and disorders associated with inhibition of neutral endopeptidase (EC 3.4.24.11) The use of such pharmaceutical compositions is also provided.

  The condition or disorder (or disease) is preferably hypertension, acute heart failure, chronic heart failure, congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation , Atrial flutter, adverse vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (unstable or stable), renal failure (diabetic and non-diabetic), heart failure, angina, diabetes Secondary aldosteronism, primary and secondary pulmonary hypertension, diabetic nephropathy, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary kidney disease, renovascular hypertension, diabetic retinopathy, It can be selected from the group consisting of migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive impairment, glaucoma and stroke.

  In a further aspect, a method for treating or preventing conditions and disorders associated with inhibition of neutral endopeptidase (EC 3.4.24.11), as described herein, in a subject in need thereof. A method comprising administering a therapeutically effective amount of a crystalline or amorphous form or a therapeutically effective amount of a pharmaceutical composition.

  In addition, a method is provided for making any one of the crystalline forms, preferably transformation B.

In addition, any one crystalline form, is preferably provided a method for producing a transformation H _B.

  Additional aspects and embodiments of the present disclosure are set forth in the following description and claims, which are hereby incorporated by reference.

FIG. 4 is an X-ray powder diffraction (XRPD) pattern of modification A. It is a figure which shows the X-ray powder diffraction (XRPD) pattern of the modification B. FIG. 4 is an X-ray powder diffraction (XRPD) pattern of Modification C. Is a diagram showing an X-ray powder diffraction (XRPD) pattern of modification _{H B.} It is a figure which shows the X-ray powder diffraction (XRPD) pattern of the amorphous calcium salt of AHU377. It is a figure which shows the thermogravimetric analysis (TGA) of the modification A. It is a figure which shows the thermogravimetric analysis (TGA) of the modification B. It is a figure which shows the thermogravimetric analysis (TGA) of the modification C. It illustrates thermal gravimetric analysis (TGA) of the transformation _{H B.} It is a figure which shows the thermogravimetric analysis (TGA) of the amorphous calcium salt of AHU377.

  The present disclosure is disclosed and characterized herein as N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R). )-Crystalline crystalline form of calcium salt of methylbutanoic acid ethyl ester (AHU377).

  Listed below are definitions of various terms used herein. The following definitions with more specific explanations of more general terms, and the preceding definitions, are intended to replace one, two, more or all of the general terms in any embodiment of the present invention. Can be used, thereby providing further preferred invention embodiments, all of which should be considered as disclosed herein.

  As used herein, “polymorph” refers to crystalline forms that have the same chemical composition but differ in the spatial arrangement of molecules, atoms, and / or ions that form a crystal.

Certain crystalline forms of the compound of formula (I) may be referred to as “crystalline form X”, “crystalline form X”, “polymorphic form X”, “modification X”, or “H _X ”. Where “X” is the letter assigned to that particular crystalline form. Corresponding names in which “X” is replaced with a specific symbol (letter or string) are used herein.

  As used herein, the term “crystalline form” refers to an anhydrous crystalline form, a partially crystalline form, a mixture of crystalline forms, a hydrate crystalline form, and a solvate crystalline form. Including.

  As used herein, the term “hydrate” refers to a crystalline form containing one or more water molecules in a three-dimensional periodic array. This can include non-stoichiometric hydrates or stoichiometric hydrates such as hemihydrate, monohydrate, dihydrate and trihydrate.

  As used herein, the term “solvate” refers to a crystalline form of molecules, atoms, and / or ions that further includes molecules of the solvent incorporated into the crystalline lattice structure. Solvent molecules in the solvate may exist in a regular and / or disordered arrangement. Solvates can contain either stoichiometric or non-stoichiometric amounts of solvent molecules. For example, a solvate having a non-stoichiometric amount of solvent molecules can result from a partial loss of solvent from the solvate. Solvates are composed of two or more molecules or N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R)-in the crystalline lattice structure. It can exist as a dimer or oligomer comprising the calcium salt of methylbutanoic acid ethyl ester (AHU377).

  Hydrates are specific variations of solvates, such as solvates with two or more solvents other than water or solvates with one or more solvents other than water in combination with water. Are included in the definition of “solvate” in the present specification.

  As used herein, the term “amorphous” refers to a solid form of molecules, atoms, and / or ions that are not crystalline. Amorphous solids do not show a clear X-ray diffraction pattern (see, for example, FIG. 5).

  As used herein, “substantially pure”, when used with respect to form, is greater than 50, 60, 70, 80 or 90% by weight of compound ABC, based on the weight of the compound, for example By 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, and for example, compounds having a purity equal to about 100% by weight are meant. The remaining material includes other forms of the compound and / or reactive impurities and / or processing impurities resulting from its preparation. For example, the crystalline form of the calcium salt of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is Which can be considered substantially pure in that it has a purity of greater than 90% by weight, as measured by means currently known and generally accepted in the art, where The remaining less than 10% by weight of the material includes other forms of compound ABC and / or reaction impurities and / or processing impurities. One prevalence of polymorphic crystalline forms can be determined by quantification of characteristic signals in X-ray powder diffraction (XRPD) and XRPD spectra.

  The term “compound of the invention” refers to N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377). Of solid forms (especially represented as compounds of formula (I)), preferably any one, a plurality or all of the modifications described in the examples. This includes anhydrous crystalline forms, partially crystalline forms, mixtures of crystalline forms, hydrate crystalline forms and solvate crystalline forms.

  The phrase “pharmaceutically acceptable” is in contact with human or animal tissue, in proportion to a reasonable benefit / risk ratio, without undue toxicity, irritation, allergic response, or other problems or complications. It is used herein to refer to compounds, materials, compositions, and / or dosage forms that are deemed suitable for use by those of skill in the art.

  Where “substantially” is used, this means that a numerical value or other feature is essentially the same as described after “substantially”, eg, ± It means 5% variation or preferably the same.

  When “20 to 25 ° C.” is used, this preferably refers to about 22 ° C., more preferably 22 ° C.

The present invention includes all crystalline forms and pharmaceutically acceptable isotopically labeled forms of the compounds of formula (I). In the isotope-labeled form, one or more atoms are replaced with atoms having the same atomic number but having an atomic mass or mass number different from the predominant atomic mass or mass number in nature. Suitable isotopes are hydrogen isotopes such as ² H and ³ H, carbon isotopes such as ¹¹ C, ¹³ C and ¹⁴ C, nitrogen isotopes such as ¹³ N and ¹⁵ N, oxygen isotopes, For example, ¹⁵ O, ¹⁷ O and ¹⁸ O are included. Certain isotopically-labelled compounds, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes, such as deuterium, i.e. ² H, can result in certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, Therefore, it may be preferable in some situations. Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are generally prepared according to the attached examples and preparations by conventional techniques known to those skilled in the art or using appropriate isotope-labeled reagents in place of previously used unlabeled reagents. Can be prepared by methods analogous to those described in.

  As used throughout this specification and in the claims, the term “treatment” encompasses all different forms or modes of treatment known to those skilled in the art, in particular, prevention, healing, progression delay and alleviation. And treatment to improve the patient's condition with respect to one or more symptoms of the disease.

Solid State Properties Different crystalline or amorphous forms can exhibit different solid state properties such as hygroscopicity, compaction behavior, stability during storage, and solid flow. These properties in turn affect the suitability of a particular solid state form as an active pharmaceutical agent for commercial production. For example, flowability affects the ease with which the material can be handled during processing into a pharmaceutical product. If the particles of the powdered compound do not flow through each other easily, the formulation specialist must take that fact into account when developing a tablet or capsule formulation, whereby a glidant such as colloidal The use of silicon dioxide, talc, starch or tricalcium phosphate may be necessary. Compressibility and / or stability under wet or dry granulation conditions is also an important feature.

  Different crystalline or amorphous forms of the same drug can also have substantial differences in pharmaceutically important properties such as dissolution rate and bioavailability. Dissolution rate is not only a consideration in formulating syrups, elixirs and other liquid pharmaceuticals, but can also have therapeutic significance. For example, the rate of dissolution of an active ingredient in a patient's gastric fluid can have therapeutic significance because it imposes an upper limit on the rate at which an orally administered active ingredient can reach the patient's bloodstream.

These practical physical properties are affected by the conformation and orientation of the molecules in the unit cell and / or the resulting crystalline form, which can define a specific polymorphic form of the material. Polymorphic forms can also give rise to thermal behavior that differs from that of amorphous materials or other polymorphic forms. Thermal behavior is measured in the laboratory by techniques such as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and is used to distinguish some polymorphic forms from others. be able to. Certain polymorphic forms can also give rise to unique spectroscopic properties that can be detected by single crystal or powder X-ray crystallography, solid state ¹³ C-NMR and ¹⁹ F-NMR spectroscopy and infrared spectroscopy. . The methods used to characterize crystalline forms also include infrared spectroscopy and melting point determination.

Crystalline Forms of Compounds of Formula (I) The present invention also provides a crystalline form of the calcium salt of AHU377, preferably from the various modifications detailed herein, preferably from modifications A, B, C and H _B. Provide a crystalline form of choice.

In one embodiment, the crystalline form modification A, B, are selected from C and H _B. In another embodiment, the crystalline form is the anhydrous / hydrate form. In another embodiment, the crystalline form is a modification B or modification H _B.

  Each transformation is characterized by, among other things, its X-ray diffraction pattern having peaks that are essentially drawn in the figure or peaks that are spaced from each other at the same distance as shown in the figure (displayed as a distance of 2θ). . Accordingly, a crystalline form selected from the various transformations detailed herein is provided, preferably characterized by having an X-ray powder diffraction pattern substantially following that shown in the corresponding figure.

  As an example, N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenyl), a form of modification B, characterized by a powder X-ray diffraction pattern substantially according to that shown in FIG. A crystalline form of the calcium salt of phenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377), which preferably has formula I, is provided.

  Alternatively, each transformation is characterized by an X-ray diffraction pattern having a characteristic peak listed in its corresponding table. In a further embodiment, the invention provides a compound of formula (I) as described herein wherein the angular variation is ± 0.3 ° 2θ, or ± 0.2 ° 2θ, or ± 0.15 ° 2θ One of the crystalline forms of

  In further embodiments, the present invention provides four, five or more or all 2θ values (± 0...) Selected from the group consisting of the 7 2θ values presented in each example at a temperature of 20 to 25 ° C. 1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 Å), the crystallinity of the compound of formula (I) described after “as an example” below or in the examples Provide one of the forms.

  For example, at a temperature of 20 to 25 ° C., 4.6, 6.0, 7.1, 9.3, 11.1, 12.0, 12.6, 14.0, 14.4, 14.7. 15.5, 16.6, 18.1, 19.6, 20.7, 21.1, 21.6, 22.5, 24.6, 25.3, 25.5, and 31.5 N- (, which is a form of transformation B, characterized by a powder X-ray diffraction pattern comprising 2θ values (± 0.1 °) selected from the group (CuKα; 45 kV, 40 mA; λ = 1.540598４０) A crystalline form of the calcium salt of 3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

  For example, at a temperature of 20 to 25 ° C., 4.6 (particularly preferred), 6.0 (particularly preferred), 12.6, 15.5, 16.6, 18.1, 19.6 and 22.5 Characterized by a powder X-ray diffraction pattern comprising four, five, six or more 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598λ) selected from the group consisting of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) in the form of modification B attached A crystalline form of the calcium salt of is provided.

  By way of example, at a temperature of 20 to 25 ° C. 7 selected from the group consisting of 4.6, 6.0, 12.6, 15.5, 16.6, 18.1, 19.6 and 22.5 N- (3-carboxyl, which is a form of modification B, characterized by a powder X-ray diffraction pattern comprising two or more 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598Å) A crystalline form of the calcium salt of -1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

  In a further embodiment, the present invention provides at least 5 2θ values (± 0.1 °) (CuKα) selected from the group consisting of the 7 2θ values presented in each example at a temperature of 20 to 25 ° C. 45 kV, 40 mA; λ = 1.540598)) and provide any of the crystalline forms of the calcium salt of AHU377 described in the Examples.

In a further embodiment, the present invention provides the following features:
(A) Four or more 2θ values (± 0.1 °) (CuKα) selected from the group consisting of seven 2θ values (± 0.1 °) presented for each transformation at a temperature of 20 to 25 ° C. An X-ray powder diffraction pattern substantially in accordance with that shown in the figure relating to XRPD or its specific transformations, including: 45 kV, 40 mA; λ = 1.540598
(B) the melting point presented for each transformation in the Examples section,
(C) AHU377 calcium salt as described in the Examples, which is in the form of a specific transformation, characterized in that it has at least one of the differential thermal analysis thermograms presented for each transformation in the Examples section One of the crystalline forms of

Thus, as an example, the following features:
(A) 4 selected from the group consisting of 4.6, 6.0, 12.6, 15.5, 16.6, 18.1, 19.6 and 22.5 at a temperature of 20 to 25 ° C. An XRPD including one or more 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598Å) or an X-ray powder diffraction pattern substantially in accordance with that shown in FIG.
(B) melting point starting at 173 ° C. (± 2.4 ° C.),
(C) a differential thermal analysis thermogram having an endotherm starting at 173 ° C. (± 2.5 ° C.),
(D) N- (3-carboxyl-1-oxopropyl)-(, which is a form of modification B, characterized by at least one thermogravimetric analysis (TGA) diagram substantially the same as shown in FIG. A crystalline form of the calcium salt of 4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

In a further aspect of the present invention, the form consisting essentially of the transformation of the calcium salt of AHU377 or substantially pure form of the transformation, and the form of, inter alia modification B or modification H _B is provided. As used herein, “consisting essentially of each modification” or “substantially pure”, when used in reference to a crystalline form, is a compound of formula (I), based on the weight of the compound. A purity of greater than 50, 60, 70, 80 or 90% by weight, such as greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, and for example, equal to about 100% by weight Means a compound having One prevalence of polymorphic crystalline forms can be determined by quantification of characteristic signals in X-ray powder diffraction (XRPD) and XRPD spectra. The remaining material includes other forms of the compound and / or reactive impurities and / or processing impurities resulting from its preparation. For example, the crystalline form of the compound of formula (I) is currently known and has a purity of greater than 90% by weight as measured by means generally accepted in the art. In which the remaining less than 10% by weight of the material comprises other forms of the compound of formula (I) and / or reaction impurities and / or processing impurities.

  In other embodiments, crystalline forms are provided that comprise at least 80, 85, 90, 95, or 99% by weight of the desired modification.

  Crystalline forms containing at least 95 or 99% by weight of the desired modification are also provided. Thus, by way of example, a crystalline form is provided comprising at least 95 or 99% by weight of each preferred modification, in particular modification B.

For example, at a temperature of 20 to 25 ° C., 3.6, 6.1, 6.4, 7.6, 8.4, 10.8, 11.3, 12.8, 14.6, 15.3 16.8, 17.8, 19.7, 20.6, 21.4, 22.5, 23.4 and 24.8 selected from the group consisting of 2θ values (± 0.1 °) (CuKα ; 45kV, 40mA; λ = 1.540598Å ) characterized by a powder X-ray diffraction pattern comprising, in the form of a transformation _{H B,} N- (3- carboxyl-1-oxopropyl) - (4S) - (p A crystalline form of the calcium salt of -phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

By way of example, from the group consisting of 3.6, 6.4, 8.4, 14.6, 15.3, 16.8, 17.8, 19.7 and 20.6 at a temperature of 20 to 25 ° C. Transformation characterized by a powder X-ray diffraction pattern comprising 4, 5, 6 or more selected 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598５) in the form of H _B, N- (3- carboxyl-1-oxopropyl) - (4S) - (p- phenylphenylmethyl) -4-amino - (2R) - calcium salt methylbutanoic acid ethyl ester (AHU377) Of crystalline forms are provided.

By way of example, from the group consisting of 3.6, 6.4, 8.4, 14.6, 15.3, 16.8, 17.8, 19.7 and 20.6 at a temperature of 20 to 25 ° C. N, which is a form of transformation H _B characterized by a powder X-ray diffraction pattern comprising seven or more selected 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598５) A crystalline form of the calcium salt of-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided. .

  In a further embodiment, the present invention provides at least 5 2θ values (± 0.1 °) (CuKα) selected from the group consisting of the 7 2θ values presented in each example at a temperature of 20 to 25 ° C. 45 kV, 40 mA; λ = 1.540598)) and provide any of the crystalline forms of the calcium salt of AHU377 described in the Examples.

Thus, as an example, the following features:
(A) from the group consisting of 3.6, 6.4, 8.4, 14.6, 15.3, 16.8, 17.8, 19.7 and 20.6 at a temperature of 20 to 25 ° C. An X-ray powder diffraction pattern comprising four or more selected 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598Å) or substantially in accordance with that shown in FIG.
(B) a melting point starting at 180 ° C. (± 2.4 ° C.),
(D) N- (3-carboxyl-, in the form of transformation H _B , characterized in that it has at least one differential thermal analysis thermogram with an endotherm starting at 180 ° C. (± 2.5 ° C.) A crystalline form of the calcium salt of 1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

  For example, at a temperature of 20 to 25 ° C., 3.6, 5.1, 10.7, 11.7, 12.2, 13.1, 15.1, 15.8, 17.3, 17.8. 2θ value (± 0.1 °) selected from the group consisting of 20.7, 21.7, 23.0, 25.0 and 26.8 (CuKα; 45 kV, 40 mA; λ = 1.540598Å) N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R), a form of modification A, characterized by an X-ray powder diffraction pattern comprising -A crystalline form of the crystalline form of the calcium salt of methylbutanoic acid ethyl ester (AHU377) is provided.

  By way of example, at a temperature of 20 to 25 ° C. 4 selected from the group consisting of 3.6, 5.1, 15.1, 15.8, 17.3, 17.8, 20.7 and 21.7 In the form of transformation A, characterized by a powder X-ray diffraction pattern comprising two, five, six or more 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598) A crystalline form of the calcium salt of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) A crystalline form is provided.

  By way of example, at a temperature of 20 to 25 ° C., 7 selected from the group consisting of 3.6, 5.1, 15.1, 15.8, 17.3, 17.8, 20.7 and 21.7 N- (3-carboxyl, which is a form of modification A, characterized by a powder X-ray diffraction pattern comprising two or more 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598Å) A crystalline form of the calcium salt of -1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

  In a further embodiment, the present invention provides at least 5 2θ values (± 0.1 °) (CuKα; selected from the group consisting of the 7 2θ values presented in each example) at a temperature of about 22 ° C. N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) described in the Examples, further characterized by a powder diffraction pattern comprising 45 kV, 40 mA; λ = 1.540598４０) ) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided in any crystalline form of the calcium salt.

As an example, the following features:
(A) four selected from the group consisting of 3.6, 5.1, 15.1, 15.8, 17.3, 17.8, 20.7 and 21.7 at a temperature of about 22 ° C. X-ray powder diffraction pattern substantially including or including the above 2θ value (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598 mm),
(B) a melting point starting at 192 ° C. (± 2.4 ° C.),
(C) N- (3-carboxyl-1-oxopropyl, which is a form of modification A, characterized by at least one differential thermal analysis thermogram having an endotherm starting at 192 ° C. (± 2.5 ° C.) A crystalline form of the calcium salt of)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

  As an example, at a temperature of 20 to 25 ° C., a 2θ value selected from the group consisting of 4.6, 6.2, 14.5, 15.4, 20.4, 21.7 and 22.1 (± 0 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598５), which is characterized by the form of modification C, N- (3-carboxyl-1-oxopropyl)-( A crystalline form of the crystalline form of the calcium salt of 4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is provided.

  As an example, at a temperature of 20 to 25 ° C., four, five selected from the group consisting of 4.6, 6.2, 14.5, 15.4, 20.4, 21.7 and 22.1 N−, which is a form of modification C, characterized by a powder X-ray diffraction pattern comprising 6 or more 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598Å) The crystalline form of the crystalline form of the calcium salt of (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (AHU377) is Provided.

  As an example, at a temperature of 20 to 25 ° C., seven 2θ values selected from the group consisting of 4.6, 6.2, 14.5, 15.4, 20.4, 21.7 and 22.1 ( N- (3-carboxyl-1-oxopropyl), a form of modification C, characterized by a powder X-ray diffraction pattern comprising (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598４０) A crystalline form of the calcium salt of-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester is provided.

Thus, as an example, the following features:
(A) 4 or more 2θ selected from the group consisting of 4.6, 6.2, 14.5, 15.4, 20.4, 21.7 and 22.1 at a temperature of 20 to 25 ° C. X-ray powder diffraction pattern comprising the value (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598Å) or substantially in accordance with that shown in FIG.
(B) a melting point starting at 180 ° C. (± 2.4 ° C.),
(C) N- (3-carboxyl-1-oxopropyl, which is a form of modification C, characterized by at least one differential thermal analysis thermogram having an endotherm starting at 180 ° C. (± 2.5 ° C.) A crystalline form of the calcium salt of)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester is provided.

  By way of example, at a temperature of 20 to 25 ° C., characterized by a powder X-ray diffraction pattern comprising a 2θ value (± 0.1 °) of 3.7 (CuKα; 45 kV, 40 mA; λ = 1.540598Å), N An amorphous form of the calcium salt of-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester is provided.

Thus, as an example, the following features:
(A) A powder X-ray diffraction pattern or characteristic peak containing a 2θ value of 3.7 (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598Å) at a temperature of 20 to 25 ° C. X-ray powder diffraction pattern substantially following that shown in FIG.
(B) a melting point starting at 204 ° C. (± 2.4 ° C.),
(C) N- (3-carboxyl-1-oxopropyl)-(4S, characterized by having at least one differential thermal analysis thermogram with an endotherm starting at 204 ° C. (± 2.5 ° C.) An amorphous form of the calcium salt of)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester is provided.

In preparing a further aspect of the crystalline form of the calcium salt of AHU377, the present invention is, AHU377 alkali metal salt, to provide a method of making a calcium salt metamorphosis _{H B} of AHU377 starting e.g. sodium salt.

In a further aspect, the present invention provides the use of a transformation H _B for generating a method for generating a transformed B starting from transformation H _B or modification B,.

The present invention provides a method for making a calcium salt modification B of AHU377 starting from AHU377 transformation _{H B.}

  In a further aspect, the present invention provides a method for producing modification B from the calcium salt of AHU377.

  In a further aspect, the present invention provides a process for producing modification A starting from an amorphous calcium salt of AHU377, or the use of an amorphous calcium salt of AHU377 to produce modification A.

  In a further aspect, the present invention provides a method of making modification C starting from an amorphous calcium salt of AHU377, or the use of an amorphous calcium salt of AHU377 to produce modification C.

  In a further aspect, the invention provides a method of making an amorphous calcium salt of AHU377 starting from the sodium salt of AHU377, or the use of the sodium salt of AHU377 to produce an amorphous calcium salt of AHU377. .

In a further aspect, the present invention provides the use of any of the crystalline forms described herein to produce another crystalline form. Preferably, modification H _B is used to produce another crystalline form, and more preferably to produce modification B.

The present invention also provides a method for preparing a transformed B, the calcium salt of AHU377, especially compounds of formula (I), for example those in the form of a transformation H _B dispersed or slurried in a solvent system, to obtain The mixture is heated to reflux, cooled, the seed of modification B is added, the suspension is stirred, the resulting solid is filtered, and the residue obtained after filtration is dried.

  Alternatively, the solvent system may be a single solvent system and the solvent comprises ethanol, preferably it is absolute ethanol, or even heptane or 2-propanol.

  Modification B can also be obtained using a method that prepares modification B using crystallization of AHU377 from a clear solution. This is a requirement imposed by some drug regulatory authorities, such as the properness of the Food and Drug Administration, in that a clear filtration from a clear solution is performed in the drug substance production step itself to remove insoluble particles. Has the main advantage of directly enabling compliance with manufacturing code (GMP) requirements.

  The same filtration can be performed prior to any other crystallization of the AHU377 calcium salt modification described herein.

Accordingly, the present invention is also a method for preparing modification B using a recrystallization method comprising:
(A) dissolving the compound of formula (I) in a solvent, preferably ethanol;
(B) heating the reaction mixture to a temperature between 60 ° C. and reflux temperature;
(C) cooling the reaction mixture to 40 to 80 ° C., for example 50 ± 5 ° C .;
(D) optionally adding a seed crystal of modification B;
(E) optionally (or preferably) stirring the reaction mixture preferably for at least 12 hours;
(F) filtering the solid from the mixture obtained at the end of step (c), (d) or (e);
(G) optionally, drying the crystals.

The present invention also uses the crystallization and recrystallization, a process for preparing a transformation H _B,
(A) concentrating a solution of AHU377 sodium salt in a solvent system by heating the reaction mixture under reduced pressure, wherein the solvent system is water;
(B) diluting the reaction mixture with water;
(C) heating the reaction mixture to 65 to 95 ° C., for example 83 ± 5 ° C .;
(D) adding an aqueous calcium chloride solution;
(E) stirring the reaction mixture at 65 to 95 ° C., such as 83 ± 5 ° C., for at least 4.5 hours;
(F) cooling the reaction mixture to 65 ± 5 ° C .;
(G) heating the reaction mixture to 65 to 95 ° C., preferably 83 ± 5 ° C .;
(H) repeating these cycles at least three times;
(I) cooling the reaction mixture to at least 40 to 80 ° C., for example 50 ± 5 ° C .;
(J) filtering the mixture obtained at the end of step (h);
(K) optionally, drying the crystals.

Accordingly, the present invention also uses the crystallization and recrystallization, a process for preparing a transformation H _B,
(A) heating a solution of AHU377 sodium salt in a solvent system, wherein the solvent system is water;
(B) adding isopropyl acetate to the reaction mixture;
(C) heating the reaction mixture to 65 to 95 ° C., for example 83 ± 5 ° C .;
(D) adding an aqueous calcium chloride solution;
(E) stirring the reaction mixture (eg, for at least 15 hours) to 50 ± 5 ° C .;
(F) filtering the mixture obtained at the end of step (e);
(G) suspending the solid obtained in step (f) in a solvent system, wherein the solvent system is water and isopropyl acetate;
(H) stirring the reaction mixture (eg, for at least 20 minutes) to 40-80 ° C., eg 50 ± 5 ° C .;
(I) filtering the mixture obtained at the end of step (h);
(J) suspending the solid obtained in step (i) in a solvent system, wherein the solvent system is water;
(K) stirring the reaction mixture for at least 20 minutes to 40-80 ° C., for example 50 ± 5 ° C .;
(L) filtering the mixture obtained at the end of step (k);
(M) optionally, drying the crystals.

Administration and Pharmaceutical Formulations The compounds of the invention are usually administered orally, intravenously, subcutaneously, buccal, rectal, transdermal, nasal, tracheal, transbronchial. And administered by any parenteral route, as an oral or nasal spray, or via inhalation. Parenteral modes of administration include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injections and infusions. Methods for their preparation suitable pharmaceutical compositions and for the delivery of compounds of the present invention, for ^{example, Remington's Pharmaceutical Sciences, 19 th} Edition, can be found in Mack Publishing Company, 1995.

  The compounds of the present invention can be administered orally. Advantageously, the compounds of the invention are orally active and may have rapid onset of activity and low toxicity. Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration where the compound enters the blood stream directly from the mouth.

  Examples of formulations suitable for oral administration include solid formulations such as tablets, microparticles, liquids or capsules containing powders, troches (including those filled with liquids), chewing agents, multi and nanoparticulates, gels, Solid solutions, liposomes, films, ovules, sprays and liquid formulations.

  Examples of liquid formulations include suspensions, solutions, syrups and elixirs. They may be used as fillers in soft or hard capsules and are typically carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or suitable oils, and one or more emulsifiers. And / or a suspending agent. Liquid formulations can also be prepared by solid reconstitution, for example from sachets.

  Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The composition may be sterilized and / or contains adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solubility enhancers, and salts and / or buffers for adjusting osmotic pressure. May be. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.

  Suitable formulations for transdermal application include a therapeutically effective amount of a compound of the invention with a carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents that aid passage through the skin of the host. Characteristically, transdermal devices have a backing member, a reservoir that optionally contains the compound with a carrier, and optionally a rate control that delivers the compound to the host skin at a controlled, predetermined rate over an extended period of time. In the form of a bandage including a barrier and means for securing the device to the skin.

  The compounds can be administered alone or as a composition in combination with pharmaceutically acceptable excipients, additives or carriers. Accordingly, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention alone or in combination with one or more pharmaceutically acceptable carriers (additives). The combination partner is, for example, an angiotensin receptor blocker (ARB), preferably ASAR selected from the group consisting of losartan, irbesartan, candesartan, eprosartan, telmisartan, olmesartan and valsartan, preferably valsartan, or pharmaceutically acceptable Or a salt thereof.

  Most preferably, compound AHU377 (sucbitryl) is a complex with valsartan, especially hexakis (4-{[(1S, 3R) -1-([1,1′-biphenyl] -4-ylmethyl) -4-ethoxy. -3-Methyl-4-oxobutyl] amino} -4-oxobutanoic acid) hexakis (N-pentanoyl-N-{[2 '-(1H-tetrazol-1-id-5-yl) [1,1'-biphenyl] ] -4-yl] methyl} -L-valine) 18-sodium-water (1/15), which can be synthesized according to WO 2007/056546. And disclosed in that document. The AHU377 calcium salt of the present invention can advantageously be used to prepare this complex.

  The compounds of the invention, for example any one of the various modifications, eg crystalline forms, are used alone or in combination with one or more carriers or additives or other pharmaceutically active ingredients Formulations can be provided to provide suitable formulations for the treatment of the indications identified above.

Examples of such carriers or additives include, but are not limited to, any one or more of the following:
a) excipients such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine,
b) Lubricants such as silica, talcum, stearic acid, its magnesium or calcium salts and / or polyethylene glycol,
c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone,
d) Disintegrants such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and e) absorbents, colorants, flavoring and / or sweetening agents.

Additional examples of useful excipients are Handbook of pharmaceutical excipients, 3rd edition, edited by AH Kibbe, published by the American Pharmaceutical Association, Washington DC, ISBN: 0-917330-96-X, or Handbook of Pharmaceutical Excipients (4 ^th edition), edited by Raymond C. Rowe, published by Science and Practice, which are incorporated herein by reference or provided solely as a basis for reference.

  Depending on the disorder to be treated and the patient and the route of administration, the compositions may be administered at equal or varying doses. In general, the daily dose range of the compounds of the invention is from about 0.0001 mg / kg to about 100 mg / kg, preferably from about 0.001 mg / kg to about 50 mg / kg, per subject body weight, in single or divided doses. Is in range. On the other hand, in some cases it may be necessary to use dosages outside these limits.

  When oral compositions are used, suitable dosage ranges for the compounds of the invention are, for example, from about 0.001 mg / kg to about 100 mg / kg of body weight of the subject in the composition per day, preferably about 0.00 per day. 01 mg to about 2000 mg. For oral administration, the composition is preferably 0.01 mg to 2000 mg, such as 0.01, 0.05, 0.1, 0.2, 0.5, 1.0, 2.5, 5, It is provided in the form of tablets containing 10, 15, 20, 25, 30, 40, 50, 75, 80 mg.

  In one embodiment, the compounds of the invention are used / formulated at a dose of 1 to 2000 mg, 1 to 1000 mg, 2 to 500 mg, 5 to 500 mg, 10 to 400 mg, or 20 to 300 mg. In another embodiment, the NEP inhibitor is used at a dose of 5, 10, 15, 20, 25, 30 40, 50, 100 or 200 mg. In a preferred embodiment, the NEP inhibitor is used at a dose of 50, 100, or 200 mg based on the amount of compound of formula (I).

  The doses quoted herein should be understood to refer to the free form (not as a salt) NEP inhibitor. If a pharmaceutically acceptable salt of a NEP inhibitor is used, the dose used should be adjusted accordingly.

  The present invention further comprises a pharmaceutical composition, preferably a tablet or gelatin capsule as described herein, comprising a second active ingredient (ie a combination partner) as described in the “Combination therapy” section below. provide.

  Accordingly, the present invention provides a pharmaceutical composition as described herein for use as a medicament. Also provided are pharmaceutical compositions described herein for use in the treatment of disorders or conditions associated with NEP inhibitory activity. Also provided are pharmaceutical compositions described herein for the manufacture of a medicament for treating a disorder or condition associated with NEP inhibitory activity.

  Also provided is a method of preventing or treating a disorder or condition associated with NEP inhibitory activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of the composition.

Uses As described above, the compounds of the invention may be useful in treating or preventing disorders or conditions mediated by NEP inhibitory activity in animals, particularly humans.

  Accordingly, the present invention is also a method for treating or preventing a condition or disorder associated with NEP inhibitory activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. Provide a way.

  Accordingly, the present invention relates to the present invention in combination with a single or another therapeutic agent (see below) for the manufacture of a medicament for treating or preventing a condition or disorder associated with NEP inhibitory activity in animals, particularly humans. The use of the compound is provided. Also provided are compounds of the invention for use in the treatment or prevention of conditions or disorders associated with NEP inhibitory activity in animals, particularly humans, alone or in combination with another therapeutic agent (see below).

[Example]
The following examples illustrate the present invention without limiting its scope.

  The following abbreviations are used herein.

  Other abbreviations used are those conventional in the art.

Methods, equipment and criteria used (i) X-ray powder diffraction (XRPD)
X-ray powder diffraction patterns were determined using a Bruker D8 discovery diffractometer instrument. X-ray diffraction patterns were recorded between 2 ° and 35 ° (2θ) using CuK radiation (45 kV, 40 mA). Measurements were performed at about 45 kV and 40 mA under the following conditions:
Scanning speed: 0.5 ° (2θ) / min Chopper increment: 0.02 °
Slit (from left to right): 2, 3, 0.3, 0.2mm

  The spectrum was recorded in reflection mode.

  The XRPD profiles for each solid form are shown in the figure.

  The characteristic peaks of the compounds of the invention are listed herein in the table below and described in the figure. The peaks listed herein are shown in degrees 2θ (± 0.2 °, preferably ± 0.1 °).

  As will be appreciated by those skilled in the art, the relative intensities of the various peaks in the table shown below are, for example, crystal orientation effects in the x-ray beam, or the purity of the material being analyzed, or the crystallinity of the sample It can vary depending on a number of factors. The peak position may also shift with respect to sample height variations, but the peak position remains substantially defined in the given table. Those skilled in the art will also recognize that measurements using different wavelengths result in different shifts according to the Bragg equation -nλ = 2d sin θ. Such alternative XRPD patterns generated by the use of alternative wavelengths still represent the same material.

(Ii) Thermogravimetric / differential thermal analysis (TG / DTA)
Differential scanning calorimetry was performed for each crystalline form using TA Instruments ™ model Q1000 (TA Instruments, New Castle, DE, USA). For each analysis, the DSC cell / sample chamber was purged with ultrapure nitrogen gas at 100 mL / min. The instrument was calibrated with high purity indium. The heating rate was 10 ° C. per minute in the temperature range between 25 and 300 ° C. The heat flow normalized by the sample weight was plotted against the measured sample temperature. Data was reported in units of watts / gram (“W / g”). The plot was created with a downward endothermic peak. The endothermic melting peak (melting point) was evaluated for the extrapolation temperature.

  As used herein, the term “add a concentrate of a given modification in a given solvent (X), another solvent (Y)” refers to a given modification of the former solvent ( It means that the solution obtained after dissolving at high concentration (> 75 mg / ml) in X) and the latter solvent (Y) are added to initiate crystallization.

Calcium salt of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid ethyl ester (calcium salt of AHU377)
By adding solid sodium hydroxide (1.9 g) to a mixture of AHU377 free acid (17.7 g) in isopropyl acetate (190 mL), AHU377 sodium salt is obtained and used directly in the preparation of the calcium salt. . The mixture is stirred at 25 ° C. for 70 minutes to give a turbid mixture. Solid calcium chloride (2.4 g) is added followed by seeding AHU377 modification B (eg, obtained as described in Example 2) at room temperature. The white suspension is stirred at 25 ° C. for 20 hours, then filtered, washed with isopropyl acetate to give solid AHU377 calcium salt after drying at 50 ° C. under reduced pressure.

Transformation B
AHU377 calcium salt (2500 g) from Example 3, 7 or 8 is suspended in absolute ethanol (60 L) at room temperature. The reaction mixture is heated to 78 ° C. (reflux) over 30 minutes and then further stirred at this temperature for 30 minutes before cooling to 50 ° C. over 30 minutes. Modification B seed crystals (2 g) are added and the suspension is stirred for 12-18 hours. The solid is filtered at 50 ° C., washed with absolute ethanol (9.5 L), and dried under reduced pressure at 60 ° C. to yield AHU377 calcium salt, modification B.

  When characterized by X-ray powder diffraction, transformation B gives the pattern shown in FIG. Characteristic peaks (± 0.1 °) are shown in the table below.

  X-ray diffraction varies with the hydration level of modification B. The above X-ray pattern is obtained under ambient conditions, ie at a temperature between 20 ° C. and 25 ° C. and a relative humidity between 40% and 65%.

  The data listed below indicates total solvent loss (LOD by thermogravimetry (TG)) and thermal transition (DTA signal) indicates the temperature at which the solvent is lost. Transformation B shows one endotherm at 173 ° C., suggesting this crystalline form.

Properties of Modification B Modification B is highly crystalline and is very slightly hygroscopic under typical humidity levels (<2% up to 75% RH). Modification B is highly crystalline and very slightly hygroscopic under typical humidity levels (<2% up to 75% RH). Modification B is thermally stable up to its melting point. The water uptake rate of transformation B can reach up to 11%. Hydrate formation was observed by wet granulation with water or equilibration of ethanol / water 1: 1 in water.

AHU377 Calcium Salt—Amorphous Synthesis A solution of AHU377 sodium salt (4.33 g) in water (40 mL) is treated with a solution of calcium chloride (0.74 g) in water (10 mL) at 25 ° C. The resulting suspension is further stirred at 25 ° C. for 2 hours and then filtered. The filter cake is washed with water (10 mL) and then dried under reduced pressure at 50 ° C. to obtain amorphous AHU377 calcium salt.

  When characterized by powder X-ray diffraction, amorphous AHU377 calcium salt gives the pattern shown in FIG. Characteristic peaks (± 0.1 °) are shown in the table below.

  The data listed below indicates total solvent loss (LOD by thermogravimetry (TG)) and thermal transition (DTA signal) indicates the temperature at which the solvent is lost. Amorphous AHU377 calcium salt shows one endotherm at 204 ° C., suggesting this form.

Properties of Amorphous AHU377 Calcium Salt Wet granulation of amorphous AHU377 calcium salt results in rapid hydrate formation. When exposed to high humidity (> 75% RH), the amorphous AHU377 calcium salt becomes a crystalline hydrate.

  Amorphous AHU377 calcium salt shows 15.2% water uptake at 80% RH. After compression or grinding for 5 minutes at 10 t, no change in amorphous morphology was observed by XRPD. Wet granulation of amorphous AHU377 calcium salt results in rapid hydrate formation. When exposed to high humidity (> 75% RH), the amorphous AHU377 calcium salt becomes a crystalline hydrate.

Synthesis of AHU377 Calcium Salt—Modification A Amorphous AHU377 calcium salt is dissolved in absolute ethanol at 25 ° C. Upon stirring at 25 ° C., precipitation of solid AHU377 calcium salt occurs. The solid is filtered and dried under reduced pressure to yield AHU377 calcium salt, modification A.

  When characterized by X-ray powder diffraction, transformation A gives the pattern shown in FIG. Characteristic peaks (± 0.1 °) are shown in the table below.

  X-ray diffraction varies with the hydration level of modification A. The above X-ray pattern is obtained under ambient conditions, ie at a temperature between 20 ° C. and 25 ° C. and a relative humidity between 40% and 65%.

  The data listed below indicates total solvent loss (LOD by thermogravimetry (TG)) and thermal transition (DTA signal) indicates the temperature at which the solvent is lost. Modification A shows one endotherm at 192 ° C., suggesting this crystalline form.

Properties of modification A Modification A is hygroscopic.

  Modification A exhibits a water uptake rate of 13.8% at 95% RH.

Synthesis of AHU377 Calcium Salt—Modification C Amorphous AHU377 calcium salt is dissolved in acetonitrile at 50 ° C. Upon stirring at 50 ° C., precipitation of solid AHU377 calcium salt occurs. The solid is filtered and dried under reduced pressure to yield AHU377 calcium salt, modification C.

  When characterized by X-ray powder diffraction, transformation C gives the pattern shown in FIG. Characteristic peaks (± 0.1 °) are shown in the table below.

  X-ray diffraction varies with the level of hydration with modification C. The above X-ray pattern is obtained under ambient conditions, ie at a temperature between 20 ° C. and 25 ° C. and a relative humidity between 40% and 65%.

  The data listed below indicates total solvent loss (LOD by thermogravimetry (TG)) and thermal transition (DTA signal) indicates the temperature at which the solvent is lost. Modification C shows one endotherm at 180.0 ° C., suggesting this crystalline form.

Synthesis of AHU377 calcium salt-modified HB, procedure 1
A solution of AHU377 sodium salt (20.37 g) in water (120 mL) (sodium salt prepared according to the procedure shown in Example 8) is concentrated under reduced pressure at 50 ° C. to remove any residual isopropyl acetate. . After concentration, the solution is diluted to the original volume with water. AHU377 sodium salt aqueous solution is heated to 83 ° C. over 30 minutes, then a solution of calcium chloride (2.61 g) in water (104 mL) is added over 1 hour. The resulting suspension is stirred at 83 ° C. for 4.5 hours. The temperature is lowered to 65 ° C. over 90 minutes and then raised again to 83 ° C. over 30 minutes. Repeat this cycle three more times. The reaction mixture is then cooled to 50 ° C. over 2 hours and further stirred at this temperature for 2 hours. The crystals are filtered off at 50 ° C. and the filter cake is washed with 50 ° C. water (2 × 65 mL). The solid was dried in vacuo at 60 ° C. to give AHU377 calcium salt, a transformation _{H B.}

When characterized by X-ray powder diffraction, transformation H _B gives a pattern shown in FIG. Characteristic peaks (± 0.1 °) are shown in the table below.

X-ray diffraction will vary with the hydration level of transformation H _B. The above X-ray pattern is obtained under ambient conditions, ie at a temperature between 20 ° C. and 25 ° C. and a relative humidity between 40% and 65%.

Transformation H _B is especially suitable for industrial scale up. This is a crystalline form that remains dry at 25 ° C. and a relative humidity ranging from 0% to 80%.

The data listed below indicates total solvent loss (LOD by thermogravimetry (TG)) and thermal transition (DTA signal) indicates the temperature at which the solvent is lost. Transformation _{H B} is 98 ° C., shows three endothermic at 134 ° C. and 180 ° C., they suggest the crystalline form.

Characteristics transformation _{H B} transformation _{H B} is obtained at the water level in the range of 1.4 to 4.1%. Complete dehydration requires heating above 97 ° C and melt cracking begins above 180 ° C. Transformation H _B shows good flow properties.

Water uptake rate of transformation _{H B} at 95% RH is 2.0%. Transformation H _B during the uptake of water and release (e.g. adsorption - in the desorption experiment) is held.

Synthesis of AHU377 calcium salt-modified HB, procedure 2
A solution of AHU377 sodium salt (20.37 g) in water (120 mL) (the sodium salt was prepared according to the procedure shown in Example 8) was heated to 50 ° C. and then isopropyl acetate (12.9 mL) was added. Added. A solution of calcium chloride (2.61 g) in water (104 mL) is added over 1 hour. The resulting suspension is stirred at 50 ° C. for 15 hours. The solid is isolated by filtration, then recharged to the reaction flask, suspended in water (240 mL) and isopropyl acetate (8 mL) and stirred at 50 ° C. for 20 minutes. The solid is isolated by filtration, then recharged to the reaction flask, suspended in water (240 mL) and stirred at 50 ° C. for 20 minutes. Filtered, and dried under reduced pressure at 60 ° C., to obtain AHU377 calcium salt, a transformation _{H B.}

AHU377 Sodium Salt For example, the sodium salt of AHU377 used in Example 3 is synthesized from AHU377 free acid by treatment with sodium hydroxide according to the following general scheme.

  In most cases, an isopropyl acetate solution of AHU377 prepared according to the method described in Example 1 is used. The sodium salt of AHU377 is generally not isolated as a pure substance, but is used as an aqueous solution after treating an isopropyl acetate solution of AHU377 with an aqueous sodium hydroxide solution.

  A solution of AHU377 free acid (88.7 g, 1.00 equiv) in isopropyl acetate (850 ml) at room temperature with a solution of sodium hydroxide (8.62 g, 1.00 equiv) in water (270 ml). Added. The biphasic mixture is heated to 50 ° C. and then stirred at this temperature for 15 minutes. After phase separation at 50 ° C., the organic layer is extracted with water (105 ml). The combined aqueous phases are washed with isopropyl acetate (2 × 255 ml) to give an aqueous solution of AHU377 sodium salt, which is used directly without further purification.

  In the examples of the present invention, the free acid of AHU377 was prepared by acylation of an amine as follows (following the scheme shown in WO 2008/031567):

  Ethyl (2R, 4S) -5-([1,1′-biphenyl] -4-yl) -4-amino-2-methylpentanoate hydrochloride (100 g, 1.00 equivalents) in isopropyl acetate (800 ml) ) (Prepared as described in US Pat. No. 5,217,996) and succinic anhydride (33.1 g, 1.15 equivalents) at 0 ° C. with isopropyl acetate ( A solution of triethylamine (51 ml, 1.28 equiv) in 100 ml) is added over 1 hour. The reaction mixture is further stirred at 0 ° C. for 1 hour and then warmed to room temperature over 1 hour. The reaction is quenched by adding a solution of citric acid (68.5 g, 1.24 equiv) in water (300 ml). After phase separation, the organic layer was washed with water (2 × 200 ml) to give a free acid solution of AHU277 in isopropyl acetate, which was used directly in the next step without further purification (see Example 8). . The free acid of AHU377 can be obtained as a pure material by concentrating an isopropyl acetate solution and used in the next step without further purification (see Example 1).

Capsules The following are examples of pharmaceutical dosage forms suitable for use in the present invention.

Preparation of 1,000 capsules each containing 50 mg AHU377 calcium salt modification B as active ingredient 50.00 g active ingredient, 187.00 g lactose, 80.00 g modified starch and 3.00 g magnesium stearate And passed through sieves each having an aperture of 0.6 mm. The drug substance is placed in a suitable mixer and mixed first with magnesium stearate and then with lactose and starch until homogeneous. No. 2 hard gelatin capsules are each filled with 300 mg of the mixture using a capsule filling machine.

Preparation of 1,000 capsules each containing 50 mg AHU377 calcium salt modification B as active ingredient 50.00 g active ingredient, 187.00 g lactose, 80.00 g modified starch and 3.00 g magnesium stearate And passed through sieves each having an aperture of 0.6 mm. The drug substance is placed in a suitable mixer and mixed first with magnesium stearate and then with lactose and starch until homogeneous. No. 2 hard gelatin capsules are each filled with 300 mg of the mixture using a capsule filling machine.
The invention described in the scope of the original claims of the present application will be added below.
[1]
Calcium salt of ethyl ester of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid in crystalline or amorphous form Solvates, especially hydrates.
[2]
Formula (I)
The calcium salt according to [1], comprising:
[3]
Modification A, B or C or a hydrate form, preferably crystalline form including modification B or hydrate form H _B, calcium salt according to [1] or [2].
[4]
The calcium salt according to [1] or [2], which is in an amorphous form.
[5]
4.6, 6.0, 7.1, 9.3, 11.1, 12.0, 12.6, 14.0, 14.4, 14.7, 15. at a temperature of 20 to 25 ° C. From the group consisting of 5, 16.6, 18.1, 19.6, 20.7, 21.1, 21.6, 22.5, 24.6, 25.3, 25.5, and 31.5 [1] or [2] which is a form of transformation B characterized by an X-ray powder diffraction pattern comprising selected 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598５) ] The crystalline form of the calcium salt as described in.
[6]
The following features:
i) 4, 5 selected from the group consisting of 4.6, 6.0, 12.6, 15.5, 16.6, 19.6 and 22.5 ° at a temperature of 20 to 25 ° C. X-ray powder diffraction pattern comprising 6 or 7 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598４０),
ii) an X-ray powder diffraction pattern substantially following the X-ray powder diffraction spectrum shown in FIG.
iii) melting point starting at 173 ± 2.4 ° C.
iv) Differential Thermal Analysis (DTA) thermogram with an endotherm starting at 173 ± 2.5 ° C.
v) a differential thermal analysis (DTA) thermogram substantially the same as shown in FIG.
vi) Thermogravimetric analysis (TGA) diagram substantially the same as shown in FIG.
The calcium salt according to [3], which is in the form of modification B, having at least one, two, three, four or more or all of
[7]
The following features:
i) from the group consisting of 3.6, 6.4, 8.4, 14.6, 15.3, 16.8, 17.8, 19.7 and 20.6 ° at a temperature of 20 to 25 ° C. An X-ray powder diffraction pattern comprising four, five or more selected 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598)
ii) an X-ray powder diffraction pattern substantially following the X-ray powder diffraction spectrum shown in FIG.
iii) melting point starting at 180 ± 2.4 ° C.
iv) differential thermal analysis (DTA) thermogram with an endotherm starting at 180 ± 2.5 ° C.,
v) Differential thermal analysis (DTA) / TGA thermogram substantially the same as shown in FIG.
At least one, two, three, and having four or more or all in the form of a transformation H _B, calcium salt according to [3].
[8]
The following features:
i) selected from the group consisting of 3.6, 5.1, 15.1, 15.8, 17.3, 17.8, 20.7 and 21.7 ° at a temperature of 20 to 25 ° C. 4 X-ray powder diffraction pattern comprising two, five or more 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598Å),
ii) an X-ray powder diffraction pattern substantially following the X-ray powder diffraction spectrum shown in FIG.
iii) melting point starting at 192 ± 2.4 ° C.
iv) Differential thermal analysis (DTA) thermogram with an endotherm starting at 192 ± 2.5 ° C.
v) Differential thermal analysis (DTA) or TGA thermogram substantially the same as shown in FIG.
The calcium salt according to [3], which is in the form of modification A, having at least one, two, three, four or more or all of
[9]
The following features:
i) 4, 5 selected from the group consisting of 4.6, 6.2, 14.5, 15.4, 20.4, 21.7 and 22.1 ° at a temperature of 20 to 25 ° C. Or an X-ray powder diffraction pattern including a 2θ value (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598Å) higher than that,
ii) an X-ray powder diffraction pattern substantially following the X-ray powder diffraction spectrum shown in FIG.
iii) melting point starting at 180 ± 2.4 ° C.
iv) differential thermal analysis (DTA) thermogram with an endotherm starting at 180 ± 2.5 ° C.,
v) a differential thermal analysis (DTA) thermogram substantially the same as shown in FIG.
vi) Thermogravimetric analysis (TGA) diagram substantially the same as shown in FIG.
Calcium salt according to [3], which is in the form of modification C, characterized in that it has at least one, two, three, four or more or all of
[10]
The following features:
i) an X-ray powder diffraction pattern substantially following the X-ray powder diffraction spectrum shown in FIG.
ii) melting point starting at 204 ± 2.4 ° C.
iii) differential thermal analysis (DTA) thermogram with an endotherm starting at 204 ± 2.5 ° C.,
Differential thermal analysis (DTA) or TGA thermogram substantially the same as shown in FIG.
Calcium salt according to [1], [2] or [4], which is in an amorphous form, characterized in that it has at least one, two, three, four or more or all of
[11]
[1] A pharmaceutical composition comprising the calcium salt according to any one of [10] and one or more pharmaceutically acceptable carriers or additives.
[12]
The crystalline form, transformation B, is selected from the transformation H _B and combinations thereof, preferably transformed B, and more preferably from substantially pure form, pharmaceutical composition according to [11] object.
[13]
Angiotensin receptor blocker (ARB), preferably in combination with ARB selected from the group consisting of losartan, irbesartan, candesartan, eprosartan, telmisartan, olmesartan and valsartan, preferably valsartan, or a pharmaceutically acceptable salt thereof, respectively In addition, the pharmaceutical composition according to any one of [11] or [12].
[14]
Hypertension, heart failure (acute and chronic), congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, harmful vascular remodeling, Myocardial infarction and its sequelae, atherosclerosis, angina (unstable or stable), renal failure (diabetic and non-diabetic), heart failure, angina, diabetes, secondary aldosteronism, primary and secondary Pulmonary hypertension, diabetic nephropathy, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary kidney disease, renovascular hypertension, diabetic retinopathy, migraine, peripheral vascular disease, Raynaud's disease, tube The calcium salt according to any one of [1] to [10] or [10] for use in the treatment of a condition or disorder selected from the group consisting of cavity hyperplasia, cognitive dysfunction, glaucoma and stroke 1] A pharmaceutical composition according to [12] or [13].
[15]
A method for producing the calcium salt of modification B according to [6],
i) dissolving the compound of formula (I) in a solvent, preferably ethanol,
ii) heating the reaction mixture to a temperature between 60 ° C. and reflux;
iii) cooling the reaction mixture to 40 to 80 ° C., preferably 50 to 80 ° C., eg 50 ± 5 ° C .;
iv) optionally adding a seed crystal of modification B;
v) stirring the reaction mixture preferably for at least 12 hours;
vi) filtering the solid obtained at the end of step (c), (d) or (e);
vii) optionally drying the resulting crystals;
Including a method.

Claims (15)

  Calcium salt of ethyl ester of N- (3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl) -4-amino- (2R) -methylbutanoic acid in crystalline or amorphous form Solvates, especially hydrates. Formula (I)
The calcium salt according to claim 1, comprising: Modification A, B or C or a hydrate form, preferably crystalline form including modification B or hydrate form H _B, calcium salt according to claim 1 or claim 2.   The calcium salt according to claim 1 or claim 2, which is in an amorphous form.   4.6, 6.0, 7.1, 9.3, 11.1, 12.0, 12.6, 14.0, 14.4, 14.7, 15. at a temperature of 20 to 25 ° C. From the group consisting of 5, 16.6, 18.1, 19.6, 20.7, 21.1, 21.6, 22.5, 24.6, 25.3, 25.5, and 31.5 3. In the form of transformation B, characterized by a powder X-ray diffraction pattern comprising selected 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598Å) Crystalline form of the described calcium salt. The following features:
i) 4, 5 selected from the group consisting of 4.6, 6.0, 12.6, 15.5, 16.6, 19.6 and 22.5 ° at a temperature of 20 to 25 ° C. X-ray powder diffraction pattern comprising 6 or 7 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598４０),
ii) an X-ray powder diffraction pattern substantially following the X-ray powder diffraction spectrum shown in FIG.
iii) melting point starting at 173 ± 2.4 ° C.
iv) Differential Thermal Analysis (DTA) thermogram with an endotherm starting at 173 ± 2.5 ° C.
v) a differential thermal analysis (DTA) thermogram substantially the same as shown in FIG.
vi) a form of transformation B, characterized by having at least one, two, three, four or more or all of the thermogravimetric analysis (TGA) diagrams substantially the same as shown in FIG. The calcium salt according to claim 3. The following features:
i) from the group consisting of 3.6, 6.4, 8.4, 14.6, 15.3, 16.8, 17.8, 19.7 and 20.6 ° at a temperature of 20 to 25 ° C. An X-ray powder diffraction pattern comprising four, five or more selected 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598)
ii) an X-ray powder diffraction pattern substantially following the X-ray powder diffraction spectrum shown in FIG.
iii) melting point starting at 180 ± 2.4 ° C.
iv) differential thermal analysis (DTA) thermogram with an endotherm starting at 180 ± 2.5 ° C.,
v) substantially at least one of the same differential thermal analysis (DTA) / TGA thermograms as those shown in FIG. 9, 2, 3, and having four or more or all, of the transformation H _B The calcium salt according to claim 3, which is in a form. The following features:
i) selected from the group consisting of 3.6, 5.1, 15.1, 15.8, 17.3, 17.8, 20.7 and 21.7 ° at a temperature of 20 to 25 ° C. 4 X-ray powder diffraction pattern comprising two, five or more 2θ values (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598Å),
ii) an X-ray powder diffraction pattern substantially following the X-ray powder diffraction spectrum shown in FIG.
iii) melting point starting at 192 ± 2.4 ° C.
iv) Differential thermal analysis (DTA) thermogram with an endotherm starting at 192 ± 2.5 ° C.
v) Form of transformation A, characterized by having at least one, two, three, four or more or all of the differential thermal analysis (DTA) or TGA thermograms substantially the same as shown in FIG. The calcium salt according to claim 3, wherein The following features:
i) 4, 5 selected from the group consisting of 4.6, 6.2, 14.5, 15.4, 20.4, 21.7 and 22.1 ° at a temperature of 20 to 25 ° C. Or an X-ray powder diffraction pattern including a 2θ value (± 0.1 °) (CuKα; 45 kV, 40 mA; λ = 1.540598Å) higher than that,
ii) an X-ray powder diffraction pattern substantially following the X-ray powder diffraction spectrum shown in FIG.
iii) melting point starting at 180 ± 2.4 ° C.
iv) differential thermal analysis (DTA) thermogram with an endotherm starting at 180 ± 2.5 ° C.,
v) a differential thermal analysis (DTA) thermogram substantially the same as shown in FIG.
vi) a form of transformation C, characterized by having at least one, two, three, four or more or all of the thermogravimetric analysis (TGA) diagrams substantially the same as those shown in FIG. The calcium salt according to claim 3. The following features:
i) an X-ray powder diffraction pattern substantially following the X-ray powder diffraction spectrum shown in FIG.
ii) melting point starting at 204 ± 2.4 ° C.
iii) differential thermal analysis (DTA) thermogram with an endotherm starting at 204 ± 2.5 ° C.,
Amorphous form characterized by having at least one, two, three, four or more or all of the differential thermal analysis (DTA) or TGA thermograms substantially the same as those shown in FIG. The calcium salt according to claim 1, 2, or 4.   A pharmaceutical composition comprising the calcium salt according to any one of claims 1 to 10 and one or more pharmaceutically acceptable carriers or additives. The crystalline form, transformation B, is selected from the transformation H _B and combinations thereof, preferably transformed B, and more preferably from substantially pure form, pharmaceutical composition according to claim 11 object.   Angiotensin receptor blocker (ARB), preferably in combination with an ARB selected from the group consisting of losartan, irbesartan, candesartan, eprosartan, telmisartan, olmesartan and valsartan, preferably valsartan, or a pharmaceutically acceptable salt thereof, respectively The pharmaceutical composition according to any one of claims 11 and 12.   Hypertension, heart failure (acute and chronic), congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, harmful vascular remodeling, Myocardial infarction and its sequelae, atherosclerosis, angina (unstable or stable), renal failure (diabetic and non-diabetic), heart failure, angina, diabetes, secondary aldosteronism, primary and secondary Pulmonary hypertension, diabetic nephropathy, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary kidney disease, renovascular hypertension, diabetic retinopathy, migraine, peripheral vascular disease, Raynaud's disease, tube 11. A calcium salt according to any one of claims 1 to 10 for use in the treatment of a condition or disorder selected from the group consisting of cavity hyperplasia, cognitive dysfunction, glaucoma and stroke. The pharmaceutical composition according to Motomeko 11,12 or 13. A method for making the calcium salt of modification B according to claim 6 comprising:
i) dissolving the compound of formula (I) in a solvent, preferably ethanol,
ii) heating the reaction mixture to a temperature between 60 ° C. and reflux;
iii) cooling the reaction mixture to 40 to 80 ° C., preferably 50 to 80 ° C., eg 50 ± 5 ° C .;
iv) optionally adding a seed crystal of modification B;
v) stirring the reaction mixture preferably for at least 12 hours;
vi) filtering the solid obtained at the end of step (c), (d) or (e);
vii) optionally, drying the resulting crystals.